Structural Insights into the Enzymes of the Trypanothione Pathway: Targets for Antileishmaniasis Drugs

Abstract

Leishmaniasis is a neglected disease that kills 60,000 people worldwide, and which is caused by the protozoa Leishmania. The enzymes of the trypanothione pathway: trypanothione synthetase-amidase, trypanothione reductase (TR) and tryparedoxin-dependent peroxidase are absent in human hosts, and are essential for parasite survival and druggable. The most promising target is trypanothione synthetase-amidase, which has been also chemically validated. However, the structural data presented in this review show that TR also should be considered as a good target. Indeed, it is strongly inhibited by silver- and gold-containing compounds, which are active against Leishmania parasites and can be used for the development of novel antileishmanial agents. Moreover, TR trypanothione-binding site is not featureless but contains a sub-pocket where inhibitors bind, potentially useful for the design of new lead compounds.

Novel Heteroaryl Selenocyanates and Diselenides as Potent Antileishmanial Agents

“…TryR catalyzes the reduction of trypanothione disulfide to trypanothione (44). Therefore, during recent years a great number of inhibitors of this key enzyme have been reported (45)(46)(47). Based on the chemical analogy of sulfur and selenium, we decided to explore the relevance of this trace element to generate new TryR inhibitors.…”

Dibenzosuberyl substituted polyamines and analogs of clomipramine as effective inhibitors of trypanothione reductase; molecular docking, and assessment of trypanocidal activities

“…The organic layers were collected, dried (anhydrous Na 2 SO 4 ) and concentrated. Purification by column chromatography (1to 4% ethyl acetate in CH 2 Cl 2 ) afforded the desired compounds (12), (13) and (14).…”

“…20,[24][25][26] Several factors make TR (EC 1.8.1.12) in particular a compelling target for the development of new chemotherapeutics. 14,15,18,27 These factors include that TR is pivotal to the redox metabolism of trypanosomatids, as it appears to be the only route for the transfer of reducing equivalents from NADPH to thiol-containing species. 7 Also, several genetic studies on Leishmania and Trypanosoma have shown the importance of TR, including studies in which trypanosomatids modified to produce decreased levels of TR were found to be acutely sensitive to oxidative stress with severely compromised abilities to infect cells.…”

“…The dithiol (T(SH) 2 ) is regenerated through the action of trypanothione reductase (TR) which utilizes NADPH to reduce T(S) 2 . [13][14][15][16] Compounds that disrupt the maintenance of levels of T(SH) 2 either through conjugation with T(SH) 2 , inhibition of the synthesis of polyamines and other components of T(SH) 2 , or inhibition of TR, have potential to be effective and selective anti-trypanosomal agents. [17][18][19] Indeed several current anti-trypanosomal drugs impact levels of T(SH) 2 in trypanosomatids, although this may not be the primary therapeutic action of these drugs.…”

“…13,35 However, TR and GR have quite different substrate specificities, TR does not reduce glutathione disulfide and GR does not reduce T(S) 2 . 36,37 A range of structurally diverse inhibitors of TR have been developed (for reviews see 14,15,17 ), with the non-metal inhibitors generally including an aromatic and an amino group (that is protonated at physiological pH). Several of these TR inhibitors are also good trypanocides in vitro (i.e., kill trypanosomatids in buffer solutions).…”